MeCP2 duplication syndrome is a severe and progressive neurological disorder caused by the duplication (or triplication) of the MeCP2 gene located on the X-chromosome. The disorder is characterized by intellectual disability, motor deficits, ataxia, epilepsy and premature death. Little is known about the molecular mechanisms underlying MeCP2 duplication syndrome and there is no treatment. We are studying this disorder using a transgenic mouse line, MeCP2-Tg, in which human MeCP2 gene locus is inserted on the X- chromosome and in which MeCP2 is expressed at 3 ? 5 times the normal level. As in humans, male but not female MeCP2-Tg mice display cognitive impairment, seizures, motor deficits, ataxia and die at 18 ? 20 weeks of age. We find that male MeCP2-Tg mice display highly elevated expression of glial fibrillary acidic protein (GFAP) and the microtubule-associated protein, Tau, in the hippocampus and cortex, but not appreciably in other brain parts. We propose that MeCP2 duplication syndrome is a neurodegenerative disorder that is triggered by elevated GFAP in astrocytes of the cortex and hippocampus leading to their dysfunction. A consequence of this is the elevation of extracellular glutamate, which increases Tau levels in neurons and promotes their death as a result of excitotoxicity. The goal of our proposal is to investigate the contributions of GFAP and Tau to the motor and cognitive deficits in MeCP2-Tg mice. This will be accomplished using cell culture models and MeCP2-Tg mice deficient in either GFAP or Tau. The specific goals of our proposal are: (1) To understand the mechanisms underlying selective neuronal vulnerability in MeCP2-Tg mice, (2) To investigate why MeCP2 duplication syndrome selectively affects males, and (3)To investigate the contribution of increased GFAP and Tau expression to neuronal death and behavioral deficits. Our research will provide a mechanistic framework for the understanding of the molecular and cellular underpinnings of MeCP2 duplication syndrome and will likely identify two proteins, the deregulation of which likely plays a key role in disease pathogenesis. If our hypothesis is correct, therapeutic approaches to lower GFAP and Tau levels will have benefit to patients with MeCP2 duplication syndrome.